DESCRIPTION: The mechanism by which the hypothalamus, and other organs, receives leptin's signal and transduce it into a pleiotypic effector response are the subjects of this proposal. The following experiments are proposed: 1) to study the origin and projections of the signaling form of the leptin receptor positive neurons in the hypothalamus, the electrophysiologic and transcriptional responses of these neurons to leptin, and their neurotransmitter profile; 2) to use the Lox-Cre system to further evaluate leptin's sites of action in the CNS and elsewhere in vivo; and 3) to study the effector response to leptin by analyzing the physiologic mechanisms by which intracerebroventricular administration of leptin leads to a reduction in adipose tissue mass.